TY - JOUR
T1 - The classical lancefield antigen of group A Streptococcus is a virulence determinant with implications for vaccine design
AU - van Sorge, Nina M.
AU - Cole, Jason N.
AU - Kuipers, Kirsten
AU - Henningham, Anna
AU - Aziz, Ramy K.
AU - Kasirer-Friede, Ana
AU - Lin, Leo
AU - Berends, Evelien T. M.
AU - Davies, Mark R.
AU - Dougan, Gordon
AU - Zhang, Fan
AU - Dahesh, Samira
AU - Shaw, Laura
AU - Gin, Jennifer
AU - Cunningham, Madeleine
AU - Merriman, Joseph A.
AU - Hütter, Julia
AU - Lepenies, Bernd
AU - Rooijakkers, Suzan H. M.
AU - Malley, Richard
AU - Walker, Mark J.
AU - Shattil, Sanford J.
AU - Schlievert, Patrick M.
AU - Choudhury, Biswa
AU - Nizet, Victor
PY - 2014/6/11
Y1 - 2014/6/11
N2 - Group A Streptococcus (GAS) is a leading cause of infection-related mortality in humans. All GAS serotypes express the Lancefield group A carbohydrate (GAC), comprising a polyrhamnose backbone with an immunodominant N-acetylglucosamine (GlcNAc) side chain, which is the basis of rapid diagnostic tests. No biological function has been attributed to this conserved antigen. Here we identify and characterize the GAC biosynthesis genes, gacA through gacL. An isogenic mutant of the glycosyltransferase gacI, which is defective for GlcNAc side-chain addition, is attenuated for virulence in two infection models, in association with increased sensitivity to neutrophil killing, platelet-derived antimicrobials in serum, and the cathelicidin antimicrobial peptide LL-37. Antibodies to GAC lacking the GlcNAc side chain and containing only polyrhamnose promoted opsonophagocytic killing of multiple GAS serotypes and protected against systemic GAS challenge after passive immunization. Thus, the Lancefield antigen plays a functional role in GAS pathogenesis, and a deeper understanding of this unique polysaccharide has implications for vaccine development. © 2014 Elsevier Inc.
AB - Group A Streptococcus (GAS) is a leading cause of infection-related mortality in humans. All GAS serotypes express the Lancefield group A carbohydrate (GAC), comprising a polyrhamnose backbone with an immunodominant N-acetylglucosamine (GlcNAc) side chain, which is the basis of rapid diagnostic tests. No biological function has been attributed to this conserved antigen. Here we identify and characterize the GAC biosynthesis genes, gacA through gacL. An isogenic mutant of the glycosyltransferase gacI, which is defective for GlcNAc side-chain addition, is attenuated for virulence in two infection models, in association with increased sensitivity to neutrophil killing, platelet-derived antimicrobials in serum, and the cathelicidin antimicrobial peptide LL-37. Antibodies to GAC lacking the GlcNAc side chain and containing only polyrhamnose promoted opsonophagocytic killing of multiple GAS serotypes and protected against systemic GAS challenge after passive immunization. Thus, the Lancefield antigen plays a functional role in GAS pathogenesis, and a deeper understanding of this unique polysaccharide has implications for vaccine development. © 2014 Elsevier Inc.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84902461165&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/24922575
U2 - https://doi.org/10.1016/j.chom.2014.05.009
DO - https://doi.org/10.1016/j.chom.2014.05.009
M3 - Article
C2 - 24922575
SN - 1931-3128
VL - 15
SP - 729
EP - 740
JO - CELL Host & Microbe
JF - CELL Host & Microbe
IS - 6
ER -